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Preclinical proof-of-concept of Antidote Therapeutics' nicotine-degrading enzyme program as a potential new treatment for nicotine addiction published in BMC Biotechnology

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Preclinical studies demonstrated that NicA2 reduces nicotine levels in blood and brain, and extinguishes nicotine self-administration in rats

Results support further investigation of optimized variants of NicA2 to treat addiction to nicotine and reduce its adverse health effects

GAITHERSBURG, Md., July 30, 2018 (GLOBE NEWSWIRE) -- Antidote Therapeutics today announced the e-publication of the preclinical proof-of-concept study of the nicotine-degrading enzyme NicA2 in well-established animal models of nicotine addiction conducted in collaboration with the Minneapolis Medical Research Foundation in BMC Biotechnology, an open access, peer-reviewed journal. The results validate the approach of using a nicotine-degrading enzyme to treat nicotine addiction and prevent relapse.

The study found that pretreatment of rats with NicA2:

  1. markedly reduced the early distribution of nicotine to the brain when nicotine was administered as a single rapid IV bolus dose (10s) equivalent to 2 cigarettes.
     
  2. reduced nicotine distribution to the brain by more than 80% when nicotine was administered as repeated IV doses at a mg/kg rate comparable to heavy cigarette smoking (equivalent to 10 cigarettes worth of nicotine over 40 minutes)  
     
  3. attenuated nicotine discrimination and nicotine reinforcement in animal behavioral models, in a dose-dependent manner, that are predictive of the efficacy of smoking cessation medications.

NicA2 rapidly reduced blood and brain nicotine concentrations when administered to rats at single or multiple nicotine doses relevant to that seen in cigarette smokers. NicA2 also led to the extinction of nicotine self-administration in a dose-dependent manner when administered to addicted rats. These data establish NicA2 as a promising new target for further optimization and development as a novel therapeutic strategy to treat addiction to nicotine and reduce its adverse health effects.

Antidote CEO Matthew Kalnik said, "These results validate this first-in-class approach for blocking nicotine's effects using a nicotine-degrading enzyme. It is remarkable that NicA2 can degrade blood and brain nicotine levels to undetectable levels within 1 minute in vivo. The results also indicate that this rapid and near complete degradation of nicotine translates into nicotine-addicted rats stopping their nicotine-seeking behavior – the rats press the lever that delivers injections of nicotine at comparable rates to saline injections."

Importantly, the near complete-blocking of nicotine's pharmacological actions is central to Antidote's clinical development strategy which is focused on smokers with an immediate medically-diagnosed need to quit smoking to slow progression of their disease. Over 5 million smokers in the U.S. with smoking–attributable diseases, such as cardiovascular or respiratory disease, or lung and other cancers continue to smoke.  The central thesis is that by blocking nicotine's effects, acute disease outcomes will improve whether or not the patients fully abstain from smoking.  Chronically, by removing the nicotine reinforcement centrally, more patients will either reduce their smoking consumption or stop altogether.

Cigarette smoking is responsible for >480,000 deaths per year in the United States. The CDC estimates direct healthcare costs due to smoking and smoking-related illness is >$133 billion/yr. Only 1:5 smokers achieve long-term abstinence using standard of care pharmacotherapies, leaving the majority still smoking and seeking alternatives.  Thus, there remains a large unmet medical need for new approaches to combat nicotine addiction and its adverse health effects.

Reference:

BMO Biotechnology. July 24, 2018. "The nicotine-degrading enzyme NicA2 reduces nicotine levels in blood, nicotine distribution to brain, and nicotine discrimination and reinforcement in rats"

Available online: https://bmcbiotechnol.biomedcentral.com/articles/10.1186/s12896-018-0457-7

About Antidote Therapeutics
Antidote Therapeutics, Inc. is a biotechnology company with a portfolio of first-in-class nicotine-blocking drugs to treat diseases caused or worsened by nicotine.

Antidote's development strategy of treating existing disease to improve medical outcomes – rather than preventing future smoking-related illnesses that may occur decades later – is significantly different from how other drugs that target nicotine's actions have been developed as aids to smoking cessation.

Unlike FDA-approved smoking cessation treatments, Antidote's candidates do not contain nicotine or interact with nicotine-receptors in the brain or body. Instead, our anti-nicotine therapeutics are designed to trap or eliminate nicotine in the blood, having the dual benefit of neutralizing nicotine's direct, harmful effects and preventing nicotine from reaching the brain, thereby reducing the addictiveness of nicotine from cigarettes, e-cigarettes, and smokeless tobacco.

The first indications for Antidote's anti-nicotine drugs are the treatment of orphan vascular diseases in smokers where nicotine plays an important role in causing disease progression, such as Buerger's Disease and Critical Limb Ischemia. 

In the future, we plan to expand the uses of our products to other smoking-related illnesses where blocking nicotine's effects will have near-term medical benefit as well as a general aid to smoking cessation.

The company was incorporated in 2013 and is based in Gaithersburg, Maryland.
A portion of this work was supported by the National Institutes of Health, National Institute on Drug Abuse (NIDA) grant R43DA044064.

www.antidotetx.com 

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